Please wait while your page loads ...

Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia

The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. The authors sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. They then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). The repeat in 20 Australian and 31 Indian index patients were also genotyped. Gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines were assayed. In the six French Canadian patients, the investigators identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion were identified. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA.

Read the Full article here
 
 


SHARE
 

Scientific News Archives

Tagged in
Scientific News

Beaker

Privacy Policy      Service Terms      Contact      Charity Navigator